Pavlovian fear conditioning is the process of acquiring an association between a novel cue and a fear eliciting stimulus. Fear extinction is the decline in responding seen when the novel cue is no longer presented with the fearful stimulus. A great deal of evidence indicates extinction of fear conditioning results in the formation of a new association that competes with, and perhaps inhibits, memory for the original association (Myers and Davis, 2007). Evidence for this view of extinction comes from the findings that after extinction fear responding can be reinstated with a reminder shock, passage of time (spontaneous recovery) or a change in context (renewal). A large amount of data highlights the central role of the amygdala in fear acquisition and extinction. Gamma amino butyric acid (GABA) is the primary inhibitory system in the brain, therefore GABAergic mechanisms within the amygdala and perhaps other brain structures may play a critical role in modulating extinction learning. GABA inhibits corticotropin releasing hormone (CRH), a well characterized neuropeptide engaged during stress. The two may interact to modulate extinction, as GABA and CRH strongly colocalize within the amygdala. We will examine the role of CRH in fear learning by manipulating CRH neuronal function through a combination of molecular, pharmacological, and viral-vector approaches to specifically alter firing of CRH containing neurons and CRH peptide expression. Together these aims will further our understanding of inhibitory regulation of CRH neurons and the role of this regulation in extinction of fear behavior. These studies will also provide for potential novel manipulations that may rescue extinction in cases of stress-related psychopathology. PUBLIC HEALTH RELEVANCE: Our findings could have great clinical relevance for the treatment of anxiety disorders, such as post traumatic stress disorder (PTSD), because a defining symptom is disruption of the inhibition of fear under safe conditions. Work proposed within this grant manipulates neural processes involved in the inhibition of fear. These findings will enhance our basic understanding of anxiety disorders as well as inform the discovery of novel pharmacological targets as tools to treat debilitating anxiety disorders.